Cyclic ADP-ribose-mediated insulin secretion and Reg, regenerating gene

J Mol Med (Berl). 1999 Jan;77(1):74-8. doi: 10.1007/s001090050305.

Abstract

Glucose is the primary stimulus of insulin secretion in pancreatic beta-cells of the islets of Langerhans. CD38 has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose from NAD+, and cyclic ADP-ribose hydrolase, which converts cyclic ADP-ribose to ADP-ribose. ATP, produced by glucose metabolism, inhibits the cyclic ADP-ribose hydrolase of CD38 and therefore causes cyclic ADP-ribose accumulation in beta-cells. Then, cyclic ADP-ribose acts as a second messenger for Ca2+ mobilization from the endoplasmic reticulum to secrete insulin. The mechanism of insulin secretion as described above is completely different from the conventional hypothesis in which Ca2+ influx from extracellular sources was assumed to play a role in insulin secretion by glucose. On the other hand, strategies for influencing the replication of islet beta-cells and the growth of the beta-cell mass may be more important for ameliorating diabetes. Reg, regenerating gene, is involved in the growth of the beta-cell mass, and Reg protein has been shown to increase the beta-cell mass in a 90% depancreatized diabetic rat model, thereby ameliorating the diabetes. CD38 is involved in the formation of cyclic ADP-ribose and is essential for the glucose sensitivity of beta-cells for insulin secretion. Therefore, CD38 gene and Reg gene will become targets for genetic engineering for diabetic beta-cells.

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • Adenosine Diphosphate Ribose / analogs & derivatives*
  • Adenosine Diphosphate Ribose / physiology
  • Animals
  • Antigens, CD*
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / physiology
  • Calcium / metabolism
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / physiology
  • Cyclic ADP-Ribose
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / prevention & control
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Lithostathine
  • Membrane Glycoproteins
  • Models, Biological
  • NAD+ Nucleosidase / genetics
  • NAD+ Nucleosidase / physiology
  • Nerve Tissue Proteins*
  • Rats
  • Second Messenger Systems / physiology*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Calcium-Binding Proteins
  • Insulin
  • Lithostathine
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • REG1A protein, human
  • Reg1a protein, rat
  • Cyclic ADP-Ribose
  • Adenosine Diphosphate Ribose
  • ADP-ribosyl Cyclase
  • CD38 protein, human
  • Cd38 protein, rat
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1
  • Calcium